Myeloid malignancies are clonal diseases of haematopoietic stem or progenitor cells. They result from genetic and epigenetic alterations that perturb key processes such as self-renewal, proliferation and differentiation. They comprise chronic stages such as myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) and acute stages, i.e. acute myeloid leukemia (AML). AML can occur de novo (˜80% of the cases) or follow a chronic stage (secondary AML). According to the karyotype, AMLs can be subdivided into AML with favourable, intermediate or unfavourable cytogenetic risk. MPNs comprise a variety of disorders such as chronic myeloid leukemia (CML) and non-CML MPNs such as polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).
It is widely accepted that initiation and progression of tumours are the results of clonal evolution, where acquired mutations promote the selection of mutant cell clones with progressively increased fitness.
Haematopoietic stem cells (HSCs) and Progenitor cells (HPCs) divide to produce blood cells by a continuous regeneration process. As the cells divide, they are prone to accumulating mutations that generally do not affect function. However, some mutations confer advantages in self-renewal, proliferation or both, resulting in clonal expansion of the cells comprising the mutations in question. Although these mutations are not necessarily carcinogenic, the accumulation of mutations in preferred clones can, eventually, lead to a carcinogenic phenotype. The frequency of such events appears to increase with age.
It has been observed that mutations in certain genes are associated with proliferating somatic clones, such as DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1 (Xie et al., Nature Medicine, published online 19 Oct. 2014; doi:10.1038/nm.3733). However, the relationship between the presence of clones comprising disruptive mutations in these genes have only been identified in 5-7% of human subjects over 70 years of age. The influence of non-disruptive mutations has not been separately analysed.
We have analysed data from whole-exome sequencing of peripheral blood cell-derived DNA from 12,380 individuals, unselected for cancer or haematological phenotypes. We identified somatic mutations based on alleles present at unusual frequencies. We used data from a Swedish national patient register to follow health outcomes for 2-7 years after DNA sampling.
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